‘North Sea’ progressive myoclonus epilepsy: phenotype of subjects with GOSR2 mutation

Abstract

We previously identified a homozygous mutation in the Golgi SNAP receptor complex 2 gene (GOSR2) in six patients with progressive myoclonus epilepsy. To define the syndrome better we analysed the clinical and electrophysiological phenotype in 12 patients with GOSR2 mutations, including six new unrelated subjects. Clinical presentation was remarkably similar with early onset ataxia (average 2 years of age), followed by myoclonic seizures at the average age of 6.5 years. Patients developed multiple seizure types, including generalized tonic clonic seizures, absence seizures and drop attacks. All patients developed scoliosis by adolescence, making this an important diagnostic clue. Additional skeletal deformities were present, including pes cavus in four patients and syndactyly in two patients. All patients had elevated serum creatine kinase levels (median 734 IU) in the context of normal muscle biopsies. Electroencephalography revealed pronounced generalized spike and wave discharges with a posterior predominance and photosensitivity in all patients, with focal EEG features seen in seven patients. The disease course showed a relentless decline; patients uniformly became wheelchair bound (mean age 13 years) and four had died during their third or early fourth decade. All 12 cases had the same variant (c.430G>T, G144W) and haplotype analyses confirmed a founder effect. The cases all came from countries bounding the North Sea, extending to the coastal region of Northern Norway. 'North Sea' progressive myoclonus epilepsy has a homogeneous clinical presentation and relentless disease course allowing ready identification from the other progressive myoclonus epilepsies.

Myoclonus epilepsy and ataxia due to KCNC1 mutation: Analysis of 20 cases and K+ channel properties

“…This is a distinguishing factor from many other PME syndromes, including some that resemble ULD at onset and lack progressive dementia. For example, in North Sea PME and AMRF, due to recessive mutations in GOSR2 and SCARB2 , respectively, death typically occurs by the fourth decade of life …”

“…ULD is also common in other founder populations in both North Africa and North America. Similarly, all known patients with GOSR2 mutation derive from countries surrounding the North Sea . With MEAK typically arising from de novo mutation, the distribution of cases should be independent of population geography.…”

Human Diseases Associated with Form and Function of the Golgi Complex

“…One final example is GOSR2 , a Golgi-resident Qb-SNARE involved in intra-Golgi trafficking, which has been linked to “North Sea” progressive myoclonus epilepsy, a progressive neurodegenerative disease associated with skeletal deformities [47,48]. The authors of this study describe a missense mutation in a glycine residue conserved across species and present in all three GOSR2 isoforms.…”

GOSR2: a progressive myoclonus epilepsy gene

“…Following this, the clinical and neurophysiological characteristics of PME associated with GOSR2 mutation were further detailed in 12 patients (including the original six patients described by Corbett et al . []); all patients had the same homozygous mutation (c.430G>T, p.Gly144Trp) (Boissé Lomax et al ., ). Interestingly, the birthplaces of all these patients (including the birthplaces of the ancestors of one Australian patient) clustered around the North Sea (hence the eponym for this type of PME of ‘North Sea progressive myoclonus epilepsy’ by Boissé Lomax et al .…”